Guanidine compounds as anesthetics and for treatment of nervous system disorders

ABSTRACT

Novel guanidine compounds having the formula 
     
       
         
         
             
             
         
       
     
     in which R 1 , R 2 , and R 4  are as defined, are effective as sodium channel dockers in neuronal mammalian cells and as anesthetics and/or analgesics, particularly local spinal and/or epidural anesthetics, for alleviation of neuropathic pain, for providing a neuroprotective effect, and for producing anti-convulsant effects.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 12/962,021, filed 7 Dec. 2010, which is a continuation of U.S. patent application Ser. No. 10/174,055, filed 17 Jun. 2002, now U.S. Pat. No. 7,868,028, issued 11 Jan. 2011.

FIELD OF THE INVENTION

This invention relates to novel compounds that possess anesthetic and/or analgesic activity, particularly activity as local anesthetics, and more particularly activity with respect to spinal, epidural and/or other somatic or autonomic nerve conduction block. These compounds have other therapeutic applications including treatment and/or prophylaxis of neuropathic pain, epilepsy, convulsions, brain or spinal cord trauma or ischemia, and stroke.

BACKGROUND OF THE INVENTION

The leading compounds currently used as local spinal or epidural anesthetics are structurally related and include lidocaine, mepivacaine, prilocaine, chloroprocaine, bupivacaine, ropivacaine and levobupivacaine. Regional anesthesia using these compounds results from inhibition of the sodium ion influx of the voltage-gated sodium channel. These compounds have been shown to bind near the cytoplasmic opening of the sodium channel.

The natural products tetrodotoxin (TTX) and saxitoxin (STX) occlude the extracellular opening of the voltage-gated sodium channel at receptor site 1 (Lipkind, G. M., et al., Biophys J, 66:1-13 (1994)). Both TTX and STX are currently available only from natural sources. TTX is found in ovaries of some puffer fish species and in the eggs of the California newt. STX is produced by dinofiagellate alga species and maybe found in mussels and other shellfish.

The biological activities of TTX and STX are highly selective. TTX binds to the voltage-gated sodium channel with a IQ of 3 to 5 nM (Colquhoun, D., et al., J Physiol, 221:533-553 (1972)) while concentrations 104-fold greater have been shown to have no discernible effect on other receptors (Hille, B., Ionic channels of excitable membranes, (1992)). Biologic activity thus derives solely from interaction with receptor site 1 of the voltage-gated sodium channel. Compounds which compete with TTX or STX for binding to site 1 of the voltage-gated sodium channel should therefore exhibit similar biological effects.

If administered intrathecally in the rat at a dose approximating 10×ED₅₀ for block of the tail-flick reflex, TTX typically effects a neuronal block that lasts between two and four days. When administered intrathecally in the rat at this dose (10×ED₅₀ for block of tail-flick reflex), TTX appears to have toxicity to neural elements indistinguishable from saline (Sakura, S., et al., Anesth Analg, 81:338-346 (1995)).

In addition to anesthetic effects, compounds affecting blockade of the voltage-gated sodium channel in general, and TTX specifically, have well documented neuroprotective properties. There is substantial evidence that potentially damaging conditions such as ischemia induce influx of sodium through TTX-sensitive channels (Fung, M. L., et al., Neurosci Lett, 275:41-44 (1999); Lysko, P. G., et al., Stroke, 25:2476-2482 (1994); Taylor, C. P., et al., Trends Pharmacol Sci, 16:309-316 (1995)). The resultant membrane depolarization impacts other voltage-sensitive mechanisms such as voltage-sensitive calcium channels, potassium channels, and glutamate release (Li, S., et al., J Neurosci, 19:RC16 (1999)). Membrane depolarization further enhances sodium entry leading to high concentrations of intracellular sodium, depletion of ATP stores, and influx of calcium via reversal of the Na⁺—Ca²⁺ exchanger. The deleterious condition need not be acute because TTX has been shown to protect motor neurons in a chronic model of glutamate toxicity developed to mimic ALS (Rothstein, J. D., et al., Proc Natl Acad Sci USA, 90:6591-6595 (1993)).

Regardless of underlying mechanism, the homeostatic, cytoprotective, and beneficial physiologic effects afforded by TTX has been demonstrated in a variety of in vitro and in vivo biological models using varied insults including vascular occlusion (Yamasaki, Y., et al., Neurosci Lett, 121:251-254 (1991)), cardiac arrest (Prenen, G. H., et al.; Exp Neural, 99:118-132 (1988)), traumatic axonal deformation (Wolf, J. A., et al., J Neurosci, 21:1923-1930 (2001)), dorsal column segment compression (Agrawal, S. K., et al., J Neurosci, 16:545-552 (1996)), anoxia (Breder, J., et al., Neuropharmacology, 39:1779-1787 (2000); Imaizumi, T., et al., J Neurotrauma, 14:299-311 (1997); Lopachin, R. M., Ann N Y Acad Sci, 890:191-203 (1999); LoPachin, R. M., et al., Neuroscience, 103:971-983 (2001); Pringle, A. K., et al., Brain Res, 755:36-46 (1997); Probert, A. W., et al., Neuropharmacology, 36:1031-1038 (1997); Stys, P. K., et al., Ann Neurol, 30:375-380 (1991); Stys, P. K., et al., J Neurosci, 12:430-439 (1992); Vomov, J. J., et al., Stroke, 25:457-464 (1994); Waxman, S. G., et al., Brain Res, 644:197-204 (1994); Weber, M. L., et al., Brain Res, 664:167-177 (1994)), glucose deprivation (Tasker, R. C., et al., J Neurosci, 12:4298-4308 (1992)) as well as excitotoxic damage induced by veratridine (Lysko, P. G., et al., Stroke, 25:2476-2482 (1994)), brevetoxins (Berman, F. W., et al., J Pharmacol Exp Ther, 290:439-444 (1999)), and NMDA receptor stimulation (Skaper, S. D., et al., J Neurochem, 76:47-55 (2001); Strijbos, P. J., et al., J Neurosci, 16:5004-5013 (1996)).

Compounds effective at blocking voltage-gated sodium channels are effective in the treatment of neuropathic pain. More specifically, TTX inhibits neuropathic ectopic activity by blockage of TTX-sensitive voltage-gated sodium channels accumulating at the site of injury (Kim, C. H., et al., Brain Res Mol Brain Res, 95:153-161 (2001); Omana-Zapata, I., et al., Pain, 72:41-49 (1997)). In-vivo administration of TTX significantly reduces allodynic behavior in a rat model (Lyu, Y. S., et al., Brain Res, 871:98-103 (2000)). Consistent with this, TTX has been used effectively to reduce neuropathic pain in patients with cancer (du Souich, P., et al., Clin. Pharmacol. Ther., 71:MPI-46 (2002)).

Voltage-gated sodium channel blockers have also been shown effective against partial and generalized tonic seizures (Catterall, W. A., Adv Neurol, 79:441-456 (1999)). More specifically, TTX has been shown to suppress seizures in rat hippocampal slices for several hours (Burack, M. A., et al., Epilepsy Res, 22:115-126 (1995)).

A compound that competes for binding to the voltage-gated sodium channel with TTX can be an anesthetic, an analgesic, a neuroprotective agent, an agent for treatment of neuropathic pain, or an anticonvulsant. Such is the case with the compounds described here.

BRIEF SUMMARY OF THE INVENTION

The invention provides a new method and new compositions for producing anesthesia or analgesia in a subject. The method comprises administering to said subject an anesthetically or analgesically effective amount of one or more compounds having the formula

in which:

R₁ is

-   -   (a) substituted or unsubstituted alkyl;     -   (b) substituted or unsubstituted cycloalkyl;     -   (c) substituted or unsubstituted alkenyl;     -   (d) adamantyl;     -   (e) substituted or unsubstituted phenyl;     -   (f) a 5- or 6-membered optionally substituted saturated or         unsaturated heterocyclic group having from one to three         heteroatoms selected from nitrogen, oxygen and sulfur;     -   (g) substituted or unsubstituted benzyl;     -   (h) a saturated or unsaturated fused ring carbocyclic group         having from 8 to 10 ring atoms; or     -   (i) CH₂XR₅, where X is oxygen, sulfur, —NH— or —CH₂— and R₅ is         substituted or unsubstituted alkyl; substituted or unsubstituted         cycloalkyl; substituted or unsubstituted phenyl; substituted or         unsubstituted benzyl; 2-carbamide-indolyl; or a 5- to 9-membered         optionally substituted saturated or unsaturated heterocyclic         group having from one to three heteroatoms selected from         nitrogen, oxygen and sulfur;     -   R₂ is     -   (a) substituted or unsubstituted alkyl;     -   (b) substituted or unsubstituted cycloalkyl;     -   (c) substituted or unsubstituted alkenyl;     -   (d) substituted or unsubstituted alkoxyalkyl     -   (e) a 5- or 6-membered optionally substituted saturated or         unsaturated heterocyclic group having from one to three         heteroatoms selected from nitrogen, oxygen and sulfur;     -   (f) —(CH₂)—R₃, where R₃ is (i) a 5- to 9-membered optionally         substituted saturated or unsaturated heterocyclic group having         from one to three heteroatoms selected from nitrogen, oxygen and         sulfur; (ii) —NR₆R₇ where R₆ and R₇ are independently selected         from hydrogen, methyl, ethyl and benzyl; or (iii) COOR₈ where R₈         is alkyl; and n is 2 or 3;     -   (g) substituted or unsubstituted phenyl;     -   (h) substituted or unsubstitutedbenzyl;     -   (j) a saturated or unsaturated fused ring carbocyclic group         having from 8 to 10 ring atoms; or     -   (k) methylene-1-naphthyl;     -   and R₄ is     -   (a) hydrogen;     -   (b) (CH₂ _(m)COOR₁₅ where R₁₅ is alkyl or substituted alkyl; and         m is 0, 1 or 2;     -   (c) CONR₁₆R₁₇ where R₁₆ and R₁₇ are independently (i)         hydrogen; (ii) alkyl or substituted alkyl; (iii)         cycloalkyl; (iv) alkoxyalkyl; (v) a 5- to 10-membered optionally         substituted saturated or unsaturated heterocyclic group having         from one to three heteroatoms selected from nitrogen, oxygen and         sulfur, (vi) a saturated or unsaturated fused ring carbocyclic         group having from 8 to 10 ring atoms; (vii) substituted or         unsubstituted phenyl; (viii) (CH₂)_(p)R₁₈ where R₁₈ is a 5-or         6-membered optionally substituted saturated or unsaturated         heterocyclic group having from one to three heteroatoms selected         from nitrogen, oxygen and sulfur, and p is 1, 2 or 3;     -   (ix) optionally substituted benzyl; or (x) an aralkyl group         comprising a chain of from 1 to 4 methylene groups substituted         by one or two phenyl groups;     -   (d) C₁—C₄ alkoxy;     -   (e) optionally substituted phenoxy;     -   (f) SO₂NR₁₉R₂₀ where R₁₉ and R₂₀ are independently hydrogen,         optionally substituted alkyl or phenyl;     -   (g) NR₂₁R₂₂;     -   (h) COR₂₃ where R₂₃ is alkyl or is NR₂₁R₂₂;     -   (j) COOR₂₃ where R₂₃ is hydrogen, alkyl, or benzyl; or     -   (k) SO₂R₂₅ where R₂₅ is alkyl or NR₂₁R₂₂;     -   wherein R₂₁ and R₂₂ are independently hydrogen, alkyl,         optionally substituted phenyl or optionally substituted benzyl;

or a pharmaceutically acceptable salt thereof.

This invention further provides pharmaceutical compositions, particularly anesthetic or analgesic compositions, containing one or more compounds as defined above, together with one or, more pharmaceutically acceptable diluents or carriers, and optionally also including other pharmaceutically suitable ingredients. In a preferred embodiment the compositions contain an effective amount of such a compound; however, the invention also includes more concentrated compositions containing these compounds that may be diluted to provide single-dosage units containing an anesthetically or analgesically effective amount. The invention further provides an effective composition according to this invention contained within a pharmaceutically acceptable container, for example one used in preparing single-dosage units of compounds for use as anesthetics or analgesics.

The invention further provides a method for blocking voltage-gated sodium channels of neuronal mammalian cells in general, and compositions for carrying out such a method, wherein the method and compositions involve use of the above-described compounds.

Compounds that modulate the function of the sodium channel have a number of therapeutic applications, including the use in anesthesia, analgesia and the treatment and/or prophylaxis of neuropathic pain, epilepsy, convulsions, brain or spinal cord ischemia, brain or spinal cord trauma, and stroke.

The invention further provides methods for providing a neuroprotective effect to a subject, and compositions for carrying out such a method, wherein the method and compositions involve use of the above-described compounds.

The invention further provides methods for treating or alleviating neuropathic pain in a subject, and compositions for carrying out such a method, wherein the method and compositions involve use of the above-described compounds.

Still further, the invention provides methods for providing an anticonvulsant treatment or effect to a subject, or for treating seizures in a subject, and compositions for carrying out such a method, wherein the method and compositions involve use of the above-described compounds.

The invention further provides processes and chemical intermediates for producing the above compounds.

DEFINITIONS

As used herein, terms have the following meanings:

Anesthetic: providing loss of sensation or numbness.

Local anesthetic: Local anesthetics produce loss of sensation or numbness in a localized area of the body. The term includes, but is not limited to, a compound or composition that, when locally administered, e.g., topically by infiltration, or when injected to make contact with a nerve, provides full or partial inhibition of sensory perception and/or motor function. Under either definition, the localized condition so induced is also referred to herein as “local anesthesia”. Local anesthesia can result, for example, from contact of an effective amount of a local anesthetic with sensory nerve processes at the site at which the painful stimulus is present, or can result from inhibition of nerve transmission at a nerve or nerves proximal to the site at which the painful stimulus is present

The mechanism by which local anesthetics induce their effect is generally thought to be based primarily upon the ability to interfere with the initiation or transmission of the nerve impulse. The duration of action of a local anesthetic is generally proportional to the time during which it is in actual contact with the nervous tissues.

Anesthetically effective amount: An amount of a compound or composition that produces an anesthetic effect, that is, a partial or total loss of sensation, inhibition of sensory perception or inhibition of motor function.

Analgesia: Reduction of pain, generally.

Analgesically effective amount: An amount of a compound or composition that produces a reduction of pain or a full elimination of pain, in a patient.

Neuroprotective: The effect of reducing, arresting or ameliorating nervous insult, and protecting, resuscitating, or reviving nervous tissue that has suffered nervous insult.

Nervous insult or “insult” refers to any damage or potentially damaging influence to nervous tissue and any disability or death resulting therefrom. The cause of nervous insult may include but is not limited to metabolic, toxic, thermal, biochemical, chemical, and apoptotic and includes without limitation, ischemia, hypoxia, glutamate abnormality and secondary effects thereof, cerebrovascular accident, trauma, surgery, pressure, mass effect, hemorrhage, radiation, vasospasm, epilepsy, myelination/demyelination process, infection, cognitive disorder, and neurodegenerative disease such as Parkinson's disease and amyotrophic lateral sclerosis (ALS).

Neuropathic pain: Pain caused by aberrant somatosensory processing in the peripheral or central nervous system. Chronic or debilitating conditions, such as post-herpetic neuralgia and phantom limb syndrome, are categorized as neuropathic pain.

Anticonvulsant: Prevention, treatment, or attenuation of seizures or convulsions due to abnormal electrical activity in the nerve cells of the brain. These seizures may be provoked such as might occur with fever or metabolic disturbance, or unprovoked as occurs in epilepsy. They may be generalized involving all of the brain, or be partial or focal, being limited to one part of the brain. They may be manifest by sudden, violent, uncontrollable contraction of muscles as may occur with generalized tonic-clonic seizures, or more subtle, such as occurs with petit mal, partial complex, or temporal lobe seizures.

Patient or subject: A human (or other animal) that is to be treated using the compounds, compositions and/or methods disclosed herein.

Alkyl, alkoxy, alkoxyalkyl, alkylthio: saturated acyclic moieties, with straight or branched chains, having the indicated number of carbon atoms. Alkyl groups are hydrocarbyl moieties; alkoxy and alkoxyalkyl groups have an oxygen atom in the chain; alkylthio groups have a sulfur atom in the chain. Examples include methyl, ethyl, and the various propyl, butyl, pentyl, hexyl and octyl groups, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl, n-propoxyethyl, methylthio, ethylthio, n-propylthio and n-butylthio.

Alkyleneoxy; alkyleneslioxy: includes methylenedioxy, —OCH₂O—, ethylenedioxy, —OCH₂CH₂O— and ethyleneoxy, —CH₂CH₂O—.

Cycloalkyl: saturated cyclic hydrocarbyl moieties, analogous to alkyl groups, having the indicated number of carbon atoms. Examples include cyclopropyl, cyclobutyl, eyclopentyl, cyclohexyl, cycloheptyl and cylooctyl.

Alkenyl: Unsaturated acyclic hydrocarbyl moieties, with straight or branched chains, containing one or more double (olefinic) bonds, and having the indicated number of carbon atoms. Examples include vinyl, allyl, isopropenyl, 2-butenyl, 1,3-butadienyl, and the various pentenyl, hexenyl and octenyl groups.

Alkyl, alkenyl cycloalkyl and other aliphatic groups may be unsubstituted or may be substituted. Typical substituents include halo, hydroxy, cyano, nitro, COOH and COOCH₃. Substituted moieties may have from one to as many substituents as are possible on the group in question. Preferably, substituted alkyl, alkenyl and cycloalkyl moieties have from 1 to 4 substituents (of course, with a maximum number of substituents possible for the group in question). In polysubstituted compounds the substituents may be the same or different, i.e. an alkyl group may be substituted with two or three different halogens, or with halo and hydroxy groups.

Aralkyl: as generally used, refers to an alkyl group having an aryl substituent. Aralkyl groups in compounds of the present invention and their compositions and uses have the general formula (CH₂)₁₋₄. Phi₁₋₂ where Ph stands for phenyl. That is, they have from 1 to 4 methylene groups in a chain, substituted by one or two phenyl groups. An example of such an aralkyl group is 3,3-diphenylpropyl.

Halo includes fluoro, chloro, bromo and iodo substituents as indicated. Where a moiety or compound includes multiple halogens, they may be the same or different; i.e. such a compound or moiety may contain two or more different halogen atoms.

Fused carbocyclic ring moieties include fully or partly unsaturated rings such as naphthyl, tetrahydronapthyl and phenyl substituted by alkylene groups having 2-4 carbon atoms. One example of the last-mentioned type of fused ring is indanyl, i.e. a phenyl ring substituted with a propylene (—CH₂CH₂CH₂—) moiety.

Heterocyclic moieties include both saturated and unsaturated cyclical moieties having the indicated number of members, or atoms, including one or more nitrogen, sulfur and/or oxygen atoms, as indicated. The remaining atoms in the ring are carbon atoms. The moieties may contain the atoms in a single ring or in a fused ring. Examples of five-membered heterocyclic rings include thienyl, furyl, tetrahydrofuryl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolidinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, triazolyl, and pyrazolidinyl. Examples of six-membered heterocyclic rings include pyridyl, pyrazinyl, pyrimidinyl, triazinyl, piperidyl, morpholinyl, pyrany I, tetrahydropyranyl, and piperazinyl.

Examples of heterocyclic moieties having more than six carbons include indolyl, quinuclidyl, quinoly I, chromanyl, benzimidazolyl, benzoxazolyl, benzothienyl, benzofuranyl, and quinolinyl.

Heterocyclic moieties may be unsubstituted or may be substituted, for instance, by from 1 to 3 groups independently selected from halo, C₁—C₄ alkyl-hydroxy, or oxo, including combinations of such substituents.

Unsaturated moieties include in the case of carbocyclic and heterocyclic rings partially unsaturated moieties such as 1,2,3,4-tetrahydropyridinyl and 2,3-dihydroindolyl, and fully unsaturated moieties such as pyridinyl and indolyl.

DETAILED DESCRIPTION OF THE INVENTION

This invention also provides anesthetic and/or analgesic compositions and methods, as well as certain novel anesthetic and/or analgesic compounds.

In one aspect, the invention provides a method for producing anesthesia or analgesia in a subject. The method comprises administering to said subject an anesthetically or analgesically effective amount of a compound having the formula

in which:

-   -   R₁ is     -   (a) substituted or unsubstituted alkyl;     -   (b) substituted or unsubstituted cycloalkyl;     -   (c) substituted or unsubstituted alkenyl;     -   (d) adamantyl;     -   (e) substituted or unsubstituted phenyl;     -   (f) a 5- or 6-membered optionally substituted saturated or         unsaturated heterocyclic group having from one to three         heteroatoms selected from nitrogen, oxygen and sulfur;     -   (g) substituted or unsubstituted benzyl;     -   (h) a saturated or unsaturated fused ring carbocyclic group         having from 8 to 10 ring atoms; or     -   (j) CH₂XR₅, where X is oxygen, sulfur, —NH— or —CH₂— and R₅ is         substituted or unsubstituted alkyl; substituted or unsubstituted         cycloalkyl; substituted or unsubstituted phenyl; substituted or         unsubstituted benzyl; 2-carbamide-indolyl; or a 5-to 9-membered         optionally substituted saturated or unsaturated heterocyclic         group having from one to three heteroatoms selected from         nitrogen, oxygen and sulfur;     -   R₂ is     -   (a) substituted or unsubstituted alkyl;     -   (b) substituted or unsubstituted cycloalkyl;     -   (c) substituted or unsubstituted alkonyl;     -   (d) substituted or unsubstituted alkoxyalkyl     -   (e) a 5- or 6-membered optionally substituted saturated or         unsaturated heterocyclic group having from one to three         heteroatoms selected from nitrogen, oxygen and sulfur;     -   —(CH₂)_(n)R₃, where R₃ is (i) a 5- to 9-membered optionally         substituted saturated or unsaturated heterocyclic group having         from one to three heteroatoms selected from nitrogen, oxygen and         sulfur; (ii) —NR₆R₇ where R₆ and R₇ are independently selected         from hydrogen, methyl, ethyl and benzyl; or (iii) COOR₈ where R₈         is alkyl; and n is 2 or 3;     -   (g) substituted or unsubstituted phenyl;     -   (h) substituted or unsubstituted benzyl;     -   (j) a saturated or unsaturated fused ring carbocyclic group         having from 8 to 10 ring atoms; or     -   (k) methylene-1-naphthyl;     -   and R₄ is     -   (a) hydrogen;     -   (b) (CH₂)_(m)COOR₁₅ where R₁₅ is alkyl or substituted alkyl; and         m is 0, 1 or 2;     -   (c) CONR₁₆R₁7 where R₁₆ and R₁₇ are independently (i)         hydrogen; (ii) alkyl or substituted alkyl; (iii)         cycloalkyl; (iv) alkoxyalkyl; (v) a 5- to 10-membered optionally         substituted saturated or unsaturated heterocyclic group having         from one to three heteroatoms selected from nitrogen, oxygen and         sulfur; (vi) a saturated or unsaturated fused ring carbocyclic         group having from 8 to 10 ring atoms; (vii) substituted or         unsubstituted phenyl; (viii) (CH₂)_(p)R₁₈ where R₁₈ is a 5-or         6-membered optionally substituted saturated or unsaturated         heterocyclic group having from one to three heteroatoms selected         from nitrogen, oxygen and sulfur, and p is 1, 2 or 3;     -   (ix) optionally substituted benzyl; or (x) an aralkyl group         comprising a chain of from 1 to 4 methylene groups substituted         by one or two phenyl groups;     -   (d) C₁—C₄ alkoxy;     -   (e) optionally substituted phenoxy;     -   (f) SO₂NR₁₉R₂₀ where R₁₉ and R₂₀ are independently hydrogen,         optionally substituted alkyl or phenyl;     -   (g) NR₂₁R₂₂;     -   (h) COR₂₃ where R₂₃ is alkyl or is NR₂₁R₂₂;     -   (j) COOR₂₃ where R₂₃ is hydrogen, alkyl, or benzyl; or     -   (k) SO₂R₂₅ where R₂₅ is alkyl or NR₂₁R₂₂;     -   wherein R₂₁ and R₂₂ are independently hydrogen, alkyl,         optionally substituted phenyl or optionally substituted benzyl;     -   or a pharmaceutically acceptable salt thereof.

In a second aspect, the invention provides pharmaceutical compositions, particularly anesthetic or analgesic compositions, containing one or more compounds as defined herein, together win one or more pharmaceutically acceptable diluents or carriers, and optionally also including other pharmaceutically suitable ingredients. In a preferred embodiment the compositions contain an effective amount of such a compound; however, the invention also includes more concentrated compositions containing these compounds that may be diluted to provide single-dosage units containing an anesthetically or analgesically effective amount. The invention further provides an effective composition according to this invention contained within a pharmaceutically acceptable container, for example one used in preparing single-dosage units of compounds for use as anesthetics or analgesics. More preferably, the invention involves compositions, particularly anesthetic and/or analgesic compositions, and anesthetic and/or analgesic methods that involve the inclusion, or the administration to a patient, respectively, of one or more compounds having the formula

in which:

-   -   R₁ is     -   (a) C₁—C₆ alkyl, optionally substituted with one or more groups         selected from halo, hydroxy, cyano, nitro, COOH and COOCH₃;     -   (b) C₂—C₆ alkenyl, optionally substituted with one or more         groups selected from halo, hydroxy, cyano, nitro, COOH and         COOCH₃; (c) C₃—C₆ cycloalkyl, optionally substituted with one or         more groups selected from halo, hydroxy, cyano, nitro, COOH and         COOCH₃;     -   (d) adamantyl;     -   (e) optionally substituted phenyl in which the substituents are         selected from mono and dihalo, mono- and di-(C₁—C₄ alkoxy),         mono- and di-(C₁—C₄ alkylthio), C₁—C₂ alkyleneoxy; C₁—C₂         alkylenedioxy, mono-and di-(C₁—C₄ alkyl), mono- and         di-(trifluoromethyl), mono- and di-(C₁—C₄ hydroxyalkyl),         mono-and di-(C₁—C₄ alkoxyalkyl), mono- and di-hydroxy, mono- and         di-cyano, mono- and di-(COCH₃), and mono- and di-NHR₂₆;     -   (f) a 5- or 6-membered saturated or unsaturated heterocyclic         group having from one to three heteroatoms selected from         nitrogen, oxygen and sulfur, optionally substituted by from 1 to         3 groups independently selected from halo, C₁—C₄ alkyl, C₁—C₄         alkoxy, oxo and hydroxy;     -   (g) optionally substituted benzyl in which the substituents are         selected from mono-and dihalo, mono- and di-(C₁—C₄ alkoxy),         mono- and di-(C₁—C₄ alkylthio), C₁—C₂ alkyleneoxy; C₁—C₂         alkylenedioxy, mono-and di-(C₁—C₄ alkyl), mono- and         di-(trifluoromethyl), mono- and di-(C₁—C₄ hydroxyalkyl),         mono-and di-(C₁—C₄ alkoxyalkyl), mono- and di-hydroxy, mono- and         di-cyano, mono- and di-(COCH₃), and mono- and di-NHR₂₆;     -   (g) naphthyl; or     -   (h) CH₂XR₅, where X is oxygen, sulfur, —NH— or —CH₂— and R₅ is         selected from     -   (i) C₁—C₆ alkyl; (ii) C₃—C₆ cycloalkyl; (iii) optionally         substituted phenyl in which the substituents are selected from         mono- and di-(C₁—C₄ alkyl), mono- and dihalo, mono- and         di-(C₁—C₄ alkoxy), C₁—C₂ alkyleneoxy, C₁—C₂ alkylenedioxy, mono-         and di(trifluoromethyl), nitro, hydroxy, mono- and di-(C₁—C₄         hydroxyalkyl), mono- and di-(C₁—C₄ alkoxyalkyl), mono- and         di-hydroxy, mono- and dicyano, mono- and di-(COCH₃) and mono-         and di-NHR₂₆; (iv) benzyl; (v) 2-carbamide-indolyl; or (vi) a 5-         to 9-membered saturated or unsaturated heterocyclic group having         from one to three heteroatoms selected from nitrogen, oxygen and         sulfur, optionally substituted by from 1 to 3 groups         independently selected from halo, C₁—C₄ alkyl, C₁—C₄ alkoxy, oxo         and hydroxy;     -   R₂ is     -   (a) C₁—C₁₂ alkyl, optionally substituted with one or more groups         selected from halo, hydroxy, cyano, nitro, COOH and COOCH₃;     -   (b) C₂—C₈ cycloalkyl, optionally substituted with one or more         groups selected from halo, hydroxy, cyano, nitro, COOH and         COOCH₃;     -   (c) C₂—C₁₂ alkenyl, optionally substituted with one or more         groups selected from halo, hydroxy, cyano, nitro, COOH and         COOCH₃;     -   (d) C₂—C₁₂ alkoxyalkyl;

(e) a 5- or 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, C₁—C₄ alkyl, C₁—C₄ alkoxy, oxo, and hydroxy;

-   -   (f) —(CH₂)_(n)R₃, where R₃ is (i) a 5- to 9-membered saturated         or unsaturated heterocyclic group having from one to three         heteroatoms selected from nitrogen, oxygen and sulfur,         optionally substituted by from 1 to 3 groups independently         selected from halo, C₁—C₄ alkyl, C₁—C₄ alkoxy, oxo, and         hydroxy; (ii) —NR₆R₇ where R₆ and R₇ are independently selected         from hydrogen, methyl, ethyl and benzyl; or (iii) COOR₈ where R₈         is C₁—C₄ alkyl; and n is 2 or 3;     -   (g) optionally substituted phenyl, where the substituents are         independently selected from mono- and di-(C₁—C₄ alkyl); mono-         and dihalo; mono-, di-, and tri-(C₁—C₄ alkoxy); mono- and         dicyano; nitro; methylsulfonyl; mono-, di-, and         tri-(trifluoromethyl); C₁—C₂ alkyleneoxy; C₁—C₂ alkylenedioxy;         —(CH₂)_(q)COOR₉ where R₉ is C₁—C₄ alkyl; or —(CH₂)_(q)NR₁₀R₁₁         where R₁₀ and R₁₁ are independently selected from hydrogen,         (C₁—C₄) alkyl, COR₁₂ where R₁₂ is C₁—C₄ alkyl, SO₂R₁₃ where R₁₃         is C₁—C₄ alkyl, or COOR₁₄ where R₁₄ is C₁—C₄ alkyl and CONR′R″;         and q is an integer from 1 to 4;     -   (h) optionally substituted benzyl, where the substituents are         selected from mono-, di-, and tri-(C₁—C₄)alkyl; mono-, di-, and         tri-halo; mono-, di-, and tri-(C₁—C₄ alkoxy); mono-, di-, and         tri-(C₁—C₄ alkylthio); mono- and di-cyano; nitro;         methylsulfonyl; mono-, di-, and tri-(trifluoromethyl); mono-,         di-, and tri-COOR′; mono-, di-, and tri-CONR′R″; mono-, di-, and         tri-NR₂₇R₂₈ where R₂₇ and R₂₈ are independently selected from         hydrogen, C₁—C₄ alkyl, acetyl, and methylsulfonyl; C₁—C₂         alkyleneoxy; C₁—C₂ alkylenedioxy; and mono-, di-, and tri-(C₁—C₆         alkoxyalkyl);     -   (j) a saturated or unsaturated fused ring carbocyclic group         having from 8 to 10 ring atoms; or     -   (k) methylene-1- or 2-naphthyl; and     -   R₄ iS     -   (a) hydrogen;     -   (b) (CH₂)_(m)COOR′ where m is 0, 1 or 2;     -   (c) CONR₁₆R₁₇ where R₁₆ and R₁₇ are independently (i)         hydrogen; (ii) C₁—C₅ alkyl optionally substituted with one or         more groups selected from halo, hydroxy, cyano, nitro, COOH and         COOCH₃; (iii) C₃—C₆ cycloalkyl; (iv) C₂—C₈ alkoxyalkyl;     -   (v) a 5- to 10-membered saturated or unsaturated heterocyclic         group having from one to three heteroatoms selected from         nitrogen, oxygen and sulfur, optionally substituted by from 1 to         3 groups independently selected from halo, hydroxy, oxo, C₁—C₄         alkyl, C₁—C₄ alkoxy, COCH₃, COOR′, and NR₂₉R₃₀ where R₂₉ and R₃₀         are independently selected from hydrogen, C₁—C₄ alkyl, acetyl,         or methylsulfonyl; (vi) a saturated or unsaturated fused ring         carbocyclic group having from 8 to 10 ring atoms;     -   (vii) (CH2)_(p)R₁₈ where R₁₈ is a 5- or 6- membered saturated or         unsaturated heterocyclic group having from 1 to 3 heteroatoms         selected from nitrogen, oxygen and sulfur, optionally         substituted by from 1 to 3 groups independently selected from         halo, hydroxy, C₁—C₄ alkyl, C₁—C₄ alkoxy and oxo, and p is 1, 2         or 3; (viii) phenyl optionally substituted by one or more groups         independently selected from mono-, di-, and tri-halo, mono-,         di-, and tri-hydroxy, mono-, di-, and tri-(C₁—C₄ alkyl), C₁—C₂         alkyleneoxy, C₁—C₂ alkylenedioxy, COOR′, and NR₂₉R₃₀ where R₂₉         and R₃₀ are independently selected from hydrogen, C₁—C₄ alkyl,         acetyl, and methylsulfonyl; (ix) optionally substituted benzyl         where the substituents are selected from mono-, di-, and         tri-(C₁—C₄ alkyl); mono-, di-, and tri-halo; mono-, di-, and         tri-(C₁—C₄ alkoxy); nitro; methylsulfonyl; mono-, di-, and         tri-(trifluoromethyl); NR′R″; C₁—C₂ alkyleneoxy; C₁—C₂         alkylenedioxy; (x) an aralkyl group comprising a chain of from 1         to 4 methylene groups substituted by one or two phenyl groups;     -   (d) C₁—C₄ alkoxy;     -   (e) optionally substituted phenoxy, where the substituents are         independently selected from mono- and di-(C₁—C₄) alkyl; mono-         and dihalo; mono-, di-, and tri-(C₁—C₄ alkoxy); cyano; nitro;         methylsulfonyl; mono-, di-, and tri-trifluoromethyl; C₁—C₂         alkyleneoxy; C₁—C₂ alkylenedioxy; —(CH₂)_(r)COOR₉ where R₉ is         C₁—C₄ alkyl; or —(CH₂)_(r)NR₃₀R₃₁ where R₃₀ and R₃₁ are         independently hydrogen, (C₁—C₄) alkyl, COR₃₂ where R₃₂ is C₁—C₄         alkyl, SO₂R₃₃ where R₃₃ is C₁—C₄ alkyl, or COOR₃₄ where R₃₄ is         C₁—C₄ alkyl;     -   (f) SO₂NR₃₅R₃₆ where R₃₅ and R₃₆ are independently hydrogen,         C₁—C₄ alkyl or phenyl; or         -   (g) NR₃₇R₃₈ where R₃₇ and R₃₈ are independently hydrogen;             C₁—C₄ alkyl; phenyl; COR₃₉ where R₃₉ is C₁—C₄ alkyl; or             SO₂R₄₀ where R₄₀ is hydrogen or C₁—C₄ alkyl;     -   wherein R₂₆ is COCH₃, SO₂CH₃, SO₂C₆H₅, COOR′ or CONR′R″; and     -   wherein R′ and R″ are independently hydrogen or C₁—C₄ alkyl; and         pharmaceutically acceptable salts thereof.

Particularly preferred compounds, compositions and methods are those:

-   -   in which R₁ is phenyl, substituted phenyl (compounds in which R₁         is unsubstituted phenyl and mono- or dihalophenyl being         especially preferred), heterocyclic groups (thienyl being         especially preferred), or CH₂XR₅, (especially preferred are         those compounds where X is oxygen and R₅ is substituted or         unsubstituted phenyl or is benzyl);     -   in which R₂ is benzyl, substituted benzyl, C₂—C₄ alkyl, or         —(CH₂)₂R₃, where R₃ is a 5- to 6-membered saturated or         unsaturated heterocyclic group having from one to three         heteroatoms selected from nitrogen, oxygen and sulfur         (2-N-piperidoethyl being most preferred of these);     -   and in which R₄ is hydrogen;     -   or in which R₁, R₂ and R₄ are combinations of these preferred         subgroups.

Table 1 below includes representative compounds of this series. A number of the compounds in this table are available from commercial or non-profit organizations that market such molecules without regard to any specific use. They are purchased for various purposes, including use as chemical intermediates or for screening for supposed activity. These compounds thus are not novel per se; however to date no pharmaceutical activity has been reported for them.

Other compounds, as indicated in Table 1, are novel. These compounds were prepared, for example, by the process described below. Their structures were confirmed by spectroscopic analysis.

The novel compounds are those

-   -   in which R₁ is phenoxymethyl and R₂ is 4-fluorobenzyl,         4-methoxybenzyl, 2-N-piperidoethyl, octyl, 1-naphthylmethyl,         n-undecyl, benzyl or 2-(N,N-dibenzylamino)ethyl;     -   in which R₁ is benzyloxymethyl,     -   in which R₁ and R₂ are both benzyl     -   and all those in which R₄ is other than hydrogen.

As shown, the compounds in Table 1 were purchased or made, and tested, in the form of salts, particularly the hydrochloride and hydrobromide salts. However, this was done for convenience, and the invention is not limited to the use of these or other salts, but encompasses the compounds per se as well as their pharmaceutically acceptable salts.

TABLE 1

Compound no./salt R₁ R₂ R4  1/hydrochloride —CH₂O(4-ClC₆H₄) benzyl H (4-chlorophenoxy- methyl)  2/hydrochloride 3,4-dichorophenyl benzyl H  3/hydrochloride —CH₂OC₆H₅ benzyl H (phenoxymethyl)  4/hydrochloride phenoxymethyl 4-methylbenzyl H  5/hydrochloride phenyl benzyl H  6/hydrochloride 2-thiophenyl benzyl H  7/hydrochloride 4-chlorophenyl benzyl H  8/hydrochloride phenoxymethyl n-butyl H  9/hydrochloride 3,4-dichlorophenyl ethyl H 10/hydrochloride 4-chlorophenoxy- n-butyl H methyl 11/hydrochloride 3,4-dichlorophenyl 4-methylbenzyl H 12/hydrochloride phenoxymethyl 4-t-butylbenzyl H 13/hydrochloride 3,4-dichlorophenyl methyl H 14/hydrochloride phenoxymethyl 4-chlorobenzyl H 15/hydrochloride 4-chlorophenoxy- 4-chlorobenzyl H methyl 16/hydrochloride 2-thienyl 2-(1-morpholino)- H ethyl 17/hydrochloride 2-thienyl ethyl H 18/hydrochloride phenyl n-butyl H 19/hydrochloride phenoxymethyl ethyl H 20/hydrochloride phenoxymethyl n-propyl H 21/hydrochloride p-chlorophenoxy- ethyl H methyl 22/hydrochloride phenoxymethyl 2-(1-piperido)ethyl H 23/hydrochloride (1-?) adamantyl methyl H 24/hydrochloride methyl benzyl H 25/hydrochloride 2-furyl 2-(1-morpholino)- H ethyl 26/hydrochloride t-butyl benzyl H 27/hydrochloride 4-methoxyphenyl methyl H 28/hydrochloride 4-methyiphenyl 2-(N,N-diethyl- H amino)ethyl 29/hydrochloride 4-chlorophenoxy- n-propyl H methyl 30/hydrochloride phenyl 2-(1-piperido)ethyl H 31/hydrochloride 3,4-dimethoxyphenyl 2-(N,N-diethyl- H amino)ethyl 32/hydrochloride 1-naphthyl 2-(1-piperido)ethyl H 33/hydrochloride phenoxymethyl 2-(1-morpholino)- H ethyl 34/hydrochloride 2-thienyl methyl H 35/hydrochloride 4-chlorophenoxy- 2-(1-morpholino)- H methyl ethyl 36/hydrochloride t-butyl allyl H 37/hydrochloride 4-ethoxyphenyl 2-(1-piperido)ethyl H 38/hydrochloride 2-thienyl 2-(1-piperido)ethyl H 39/hydrochloride 4-bromophenyl allyl H 40/hydrochloride 4-chlorophenoxy- 2-(1-piperido)ethyl H methyl 41/hydrochloride phenoxymethyl allyl H 42/hydrochloride 3,4-dichlorophenyl 2-(N,N-diethyl- H amino)ethyl 43/hydrochloride phenyl n-propyl H 44/hydrochloride phenoxymethyl methyl H 45/hydrochloride 4-methoxyphenyl 2-(1-piperido)ethyl H 46/hydrochloride 4-chlorophenoxy- allyl H methyl 47/hydrochloride 4-methoxyphenyl benzyl H 48/hydrochloride 4-chlorophenyl n-propyl H 49/hydrochloride 4-ethoxyphenyl allyl H 50/hydrochloride 4-methylphenyl allyl H 51/hydrochloride 3,4-dichlorophenyl 2-(N,N-dimethyl- H amino)ethyl 52/hydrochloride 4-chlorophenoxy- 4-methylbenzyl H methyl 53/hydrochloride 4-chlorophenyl n-butyl H 54/hydrochloride 4-chlorophenyl methyl H 55/hydrochloride phenoxymethyl 2-(N,N-diethyl- H aminoethyl] 56/hydrochloride 4-chlorophenoxy- 2-(N,N-diethyl- H methyl aminoethyl] 57/hydrochloride 4-chlorophenoxy- methyl H methyl 58/hydrochloride 1-naphthyl methyl H 59/hydrochloride t-butyl 4-chlorobenzyl H 60/hydrochloride 4-methylphenyl n-propyl H 61/hydrochloride methyl n-propyl H 62/hydrochloride 4-bromophenyl n-butyl H 63/hydrochloride 4-bromophenyl benzyl H 64/hydrochloride p-chlorophenyl allyl H 65/hydrochloride phenyl methyl H 66/hydrochloride methyl methyl H 67/hydrochloride 2-furyl benzyl H 68/hydrochloride 2-furyl 4-chlorobenzyl H 69/hydrochloride t-butyl 2-(1-piperido)ethyl H Novel Compounds 70/hydrobromide phenoxymethyl 4-fluorobenzyl H 71/hydrobromide —CH₂OCH₂C₆H₅ benzyl H (benzyloxymethyl) 72/hydrobromide phenoxymethyl n-octyl H 73/hydrobromide phenoxymethyl methylene-1- H naphthyl 74/hydrobromide phenoxymethyl n-undecyl H 75/hydrobromide phenoxymethyl benzyl —CO₂C₂H₅ 76/hydrobromide phenoxymethyl 2-(N,N-dibenzyl- H amino)ethyl 77/hydrobromide benzyl benzyl H 78/hydrobromide phenoxymethyl 4-methoxybenzyl H

Process: In general, the compounds of this invention may be prepared by a stepwise alkylation of 2-aminobenzimidazole or a ring-substituted 2-aminobenzimidazole where R₄ is other than hydrogen.

In the first alkylation, the sodium salt of 2-aminobenzimidazole reacts smoothly with alkyl and benzyl chlorides (Joseph, L., J Med Chem, 28:601 (1963); Ogura, H., et al., J Med Chem, 15:923-926 (1972)). The second alkylation proceeds under conditions of high concentration in refluxing toluene, reacting exclusively at the 3-position of the imidazole moiety (Rehse, K., et al., Arch Pharm (Weinheim), 328:77-80 (1995)). The precipitation of the product as the hydrobromide salt prohibits additional alkylation and simplifies the purification. Yields after crystallization are low, but sufficient.

Alternatively, as described below with respect to the preparation of a combinatorial library, the compounds can be prepared by a process in which a resin-bound 4-fluoro-3-nitroarene is reacted with an amine having the formula R₂—NH₂, reduced with tin(II) chloride (Bellamy, F. D., et al., Tetrahedron Lett, 25:839-842 (1984)), cyclized with cyanogen bromide (U.S. Pat. No. 4,002,623), and reacted with a mono-substituted epoxide:

If R₄ is a group having the formula CONR₁₆R₁₇, that group is first introduced by amide coupling with the fluoronitrobenzoic acid.

Compositions: For pharmaceutical use, the compounds are incorporated into compositions or formulations. The compositions will contain pharmaceutically acceptable diluents and/or carriers, i.e. diluents or carriers that are biocompatible and free from undesirable impurities.

For administration by injection and/or infiltration or infusion, the compositions or formulations according to the invention may be suspended or dissolved as known in the art in a vehicle suitable for injection and/or infiltration or infusion. Such vehicles include isotonic saline, buffered or unbuffered and the like. Depending on the intended use, they also may contain other ingredients, including other active ingredients. For example, the compositions may contain augmenting agents for potentiating or prolonging the anesthetic activity, such as those described in U.S. Pat. No. 6,248,345, or ingredients such as isotonicity agents, sodium chloride, pH modifiers, colorants, preservatives, antibodies, enzymes, antibiotics, antifungals, antivirals, other anti-infective agents, and/or diagnostic aids such as radio-opaque dyes, radiolabeled agents, and the like, as known in the art.

However, the compositions of this invention may comprise no more than a simple solution or suspension of a compound or compounds, or a pharmaceutically acceptable salt of a compound, or combination of salts of compounds, in distilled water or in saline.

The compositions may also be in the form of controlled release or sustained release compositions as known in the art, for instance, in matrices of biodegradable or non-biodegradable injectable polymeric microspheres or microcapsules, in liposomes, in emulsions, and the like, for example, as described in U.S. Pat. No. 6,248,345.

For use, the compositions may be prepared in unit dosage forms that are sterilized and then placed within a container such as an ampoule. For instance, for use as a local anesthetic, an amount of such a composition containing an anesthetically or and/or analgesically effective amount of a compound of this invention, i.e. one sufficient to induce anesthesia or analgesia in a patient, is sterilized and placed in such a container.

The compositions of this invention may, as stated above, be prepared in the form of single-dosage units for direct administration to a patient. However, more concentrated compositions may be prepared, from which the more dilute single-unit compositions may then be produced. The more concentrated compositions thus will contain substantially more than an anesthetically or analgesically effective amount of the compound in question.

The novel compounds of this invention may be used per se, or in the form of their pharmaceutically acceptable salts, such as hydrochlorides, hydrobromides, acetates, sulfates, citrates, carbonates, trifluoroacetates and the like. The term “pharmaceutically acceptable salts” is meant to include salts of the compounds in question that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, salts can be obtained by addition of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or the like. When compounds of the present invention contain relatively basic functionalities, salts can be obtained by addition of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).

Compositions will typically contain a single anesthetic or analgesic compound of this invention. However, in some cases it may be advantageous to use a combination of two or more of such compounds; thus the compositions may contain more than one such compound.

Administration: For use as anesthetics, particularly local anesthetics, the compounds (in the form of their compositions) are administered to patients by the usual means known in the art, for example, by injection, infusion, infiltration, irrigation, topically and the like. Injection or infusion can be carried out acutely, or if prolonged local effects are desired, localized anesthetic agents can be administered continuously by means of a gravity drip or infusion pump. When used for perioperative pain control, administration may be done prior to surgery, at the time of surgery, or following surgery, and preceding, during or following administration or effect of a systemic anesthetic. Solid formulations may be shaped to fit a particular location, e.g., articular joints, then surgically placed into a site where release of local anesthetic agent is desired.

If a combination of two or more compounds of this invention is to be administered, they preferably are administered simultaneously, either in the form of a single composition or in separate compositions. They preferably are administered using the same route of administration, but this is not always necessary. For example, two compounds of the invention may be administered together via intramuscular injection or intravenously, or one compound may be administered by intramuscular injection and the other intravenously. Other routes of administration, for example oral or parenteral (intravenous, intramuscular or subcutaneous injection) may be used, as well as direct injection to the central nervous system (intrathecally).

The compounds and compositions of this invention are particularly suitable for use as local spinal and/or epidural anesthetics; however, they may be useful elsewhere as local anesthetics. Thus, formulations of this invention may be administered to intra-articular joints and bursa, and to body spaces or cavities, including pleura, peritoneum, cranium, mediastinum, and pericardium. In a preferred embodiment, potential applications include any condition for which localized anesthesia is desirable.

The uses of the compositions of this invention include both local anesthesia for the relief of pain and motor symptoms as well as local anesthesia for other medical purposes. Other applications include providing localized temporary sympathectomy, e.g., blockade of sympathetic or parasympathetic ganglia to treat a variety of autonomic diseases, including circulatory dysfunction or trigeminal neuralgia. The formulations may also be used to provide a temporary nerve block to treat localized muscle spasm and treatment of retrobulbar conditions, e.g., eye pain.

The uses of the compositions of this invention further include the treatment and/or prophylaxis of neural injury, degeneration, or death. Conditions or disorders suitable for treatment may be acute in onset such as occurs in traumatic brain injury, or chronic or insidious as may occur in neurodegenerative disorders such as ALS. These conditions may be widespread such as occurs in global ischemia following cardiac arrest, drowning, or carbon monoxide poisoning, may be restricted to or preferentially affect specific populations of susceptible neurons, or may involve discrete areas of the nervous system as may occur with stroke resulting from disruption of regional blood flow.

EXAMPLES

The following examples are provided by way of illustration only and not by way of limitation. Those of skill will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results.

Example 1 Synthesis of 1-benzyl-2-imino-3-(2-hydroxy-3-phenoxypropyl)benzimidazole hydrobromide (1) (Compound #3)

2-amino-1-benzylbenzimidazole (3)

To a solution of 2-aminobenzimidazole (2) (Aldrich, 6 g., 45 mmol) in EtOH (10 mL) was added EtONa (21% in EtOH, 16.83 mL, 45 mmol) and benzyl chloride (5.70 mL, 50 mmol) and the brown solution was refluxed for 3 days under N2 gas. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated in vacuo. The resulting brown solid was filtered hot in 300 mL acetone and crystallized from approximately 100 mL of acetone, and gave 3 as brown crystals (3.91 g., 39%). Recrystallization of the mother liquor afforded additional 3 as brown crystals (0.70 g., 7%). ¹H-NMR (DMSO-d₆) δ 5.27 (s, 2H), 6.61 (s, 2H), 6.82 (t, J=8.8 Hz, 1H), 6.93 (t, J=6.4 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.15 (d, 7.2 Hz, 1H), 7.20 (d, 6.8 Hz, 2H), 7.24 (d, 7.6 Hz, 1H), 7.31 (t, 7.6 Hz, 2H); ¹³C-NMR (DMSO-d₆) 45.11, 108.30, 115.19, 118.49, 120.88, 127.39, 127.66, 128.91, 134.60, 137.64, 143.34, 155.46.

1-bromo-3-phenoxy-propan-2-ol (5)

To a room temperature water cooled solution of allyl phenyl ether (4) (Aldrich, 1.00 g., 7.45 mmol) in 5 mL DMSO: H₂O (4:1) was added NBS (1.45 g., 8.15 mmol) as a solid. After 5-10 minutes, the reaction was added to a separation funnel with 100 mL Et₂O and washed three times with 100 mL water, then 100 mL brine solution. The ether layer was dried over MgSO₄ and concentrated in vacuo to yield a pale yellow oil (1.59 g., 92%), which was used as is without further purification.

1-benzyl-2-imino-3-(2-hydroxy-3-phenoxypropyl)benzimidazole hydrobromide (1)

To a solution of 1-bromo-3-phenoxy-propan-2-ol (5) (248 mg., 1.07 mmol.) in toluene (2 mL.) was added 2-amino-1-benzylbenzimidazole (3) (200 mg., 0.90 mmol) and the mixture was heated at reflux overnight under N₂ gas. The reaction mixture was cooled to room temperature and filtered. Crystallization of the collected solid from isopropanol gave 1 as white crystals (85 mg., 23%). Recrystallization of the mother liquor afforded additional 1 as white crystals (70 mg., 19%). ¹H-NMR (DMSO-d₆) δ 4.12 (s, 2H), 4.33 (s, 1H), 4.43 (s, 2H), 5.57 (s, 2H), 6.96 (m, 3H), 7.21-7.38 (m, 10H), 7.46 (d, J=8.0 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 9.18 (s, 2 1H); ¹³C-NMR (DMSO-d₆) δ 45.58, 46.10, 66.54, 69.43, 110.53, 111.11, 120.71, 123.39, 123.47, 127.11, 127.91, 128.72, 129.39, 129.45, 130.39, 134.56, 150.27, 157.67, 158.33.

Example 2 Preparation of Library of Compounds using a Combinatorial Method

A library of compounds in which R4 was various groups having the formula CONHR₁₇ was prepared by the process described above using 4-fluoro-3-nitrobenzoic acid, as follows:

Aldehyde resin was mixed with a primary amine (R₁₇—NH₂) in dichloroethane (DCE), triethylorthoformate (TEOF), and DMF (containing 1% acetic acid) in a 1:1:1 ratio. After shaken overnight, sodium triacetoxyborohydride (20 eq.) dissolved in DMF was added (Abdel-Magid, A. F., et al., Tetrahedron Lett, 31:5595-5598 (1990)). After the mixture was shaken at room temperature overnight, the resin was filtered and washed with DMF (3×5 mL), MeOH (3×5 mL), DMF (3×5 mL), MeOH (3×5 mL), and CH₂Cl₂ (3×5 mL). The resin was washed twice with 5 mL DMF containing 1% Hunig's base. To the filtered resin was added a mixture of 4-fluoro-3-nitrobenzoic acid (FNBA, 10 eq.) and diisopropylcarbodiimide (DIC, 5 eq.) in 2:1 DMF:DCM. After shaking at room temperature overnight, the resin was filtered and washed with DMF (3×5 mL) and CH₂Cl₂ (3×5 mL).

The resin was shaken with a primary amine (R₂—NH₂) in DMF for 8 hrs, filtered, and washed with DMF (6×5 mL), MeOH (3×5 mL), and CH₂Cl₂ (3×5 mL). The aryl nitro group was reduced by the addition of tin(II) chloride dihydrate (20 eq., >2 M) and N-methyl morpholine (NMM, 20 eq.) in N-methyl pyrrolidinone (NMP). After shaken at room temperature overnight, the resin was filtered and washed with NMP (3×5 mL), MeOH (3×5 mL), and CH₂Cl₂ (3×5 mL). The resulting resin was shaken at room temperature with cyanogen bromide (5 eq.) overnight, filtered, and washed with CH₂Cl₂ (3×5 mL), MeOH (3×5 mL), and CH₂Cl₂ (3×5 mL). To produce a free amine, the resin was shaken for 30 min. in CH₂Cl₂ with the addition of sodium methoxide in methanol, filtered, and washed with CH₂Cl₂ (4×5 mL).

In the final diversification step, the resin was heated at 50° C. in DMF with a mono-substituted epoxide [R₁CH(—CH₂O—)]. After shaking for 2 to 4 days the resin was filtered and washed with DMF (5×5 mL), MeOH (3×5 mL), and CH₂Cl₂ (3×5 mL). The resin-bound benzimidazole was cleaved from the solid-support by treatment with TFA:CH₂Cl₂ (2:3) for 1 hour at room temperature. The library contained a total of 10,560 compounds, prepared using 32 species of group R₁₇, 33 of group R₂ and 10 of group R₁. The library of compounds is depicted in Table 2:

TABLE 2

# Structure R Group Common Name 1 —CH₃ 17 methyl 2 —CH₂CH₃ 17 ethyl 3 —CH₂CH₂CH₃ 17 propyl 4

17 3-pyrazolyl 5

17 cyclopentyl 6 —Ph 17 phenyl 7

17 2-pyrimidinyl 8

17 furfuryl 9

17 tetrahydrofurfuryl 10

17 3-keto-4,5-dihydro- isoxazolyl 11 —CH₂CH₂OCH₂CH₂CH₃ 17 propoxyethyl 12 —Bn 17 benzyl 13

17 picolyl 14

17 2-thienyl 15 —CH₂CH₂N(CH₂)₄ 17 N-ethyl-pyrrolidine 16 —CH₂CH₂COOCH₂CH₃ 17 propoxylate ethyl ester 17 —Bn-4-Me 17 4-methylbenzyl 18

17 2-(1-methyl- pyrrolidinyl)ethyl 19

17 2-(1-morpholino)ethyl 20 —Bn-3-OMe 17 3-methoxybenzyl 21 —Bn-3-Cl 17 3-chlorobenzyl 22

17 3-(1-pyrrolidinyl-2- one)-propyl 23 —Bn-4-NMe₂ 17 4-(dimethylarnino)- benzyl 24

17 piperonyl 25 —Bn-4-NO₂ 17 4-nitrobenzyl 26

17 3-4-methyl-1- piperazinyl)-propyl 27

17 2-methyl-4-quinolinyl 28 —Bn-3-CF₃ 17 3-trifluoromethyl benzyl 29 —Bn-2,6-Cl 17 2,6-dichlorobenzyl 30 —Bn-4-SO₂Me 17 4-(methylsulfonyl)- benzyl 31 —Bn-3,4,5-OMe 17 3,4,5-trimethoxy- benzyl 32 —CH₂CH₂CHPh₂ 17 3,3-cliphenylpropyl 1 —CH(CH₃)₂ 2 isopropyl 2 —CH₂CH₂OH 2 2-hydroxyethyl 3

2 3-pyrazolyl 4 —CH₂CH₂CH(CH₃)₂ 2 isopentyl 5 —Ph 2 phenyl 6

2 3-pyridyl 7

2 2-pyrimidinyl 8

2 furfuryl 9

2 cyclohexyl 10

2 N-piperidinyl 11

2 tetrahydrofurfuryl 12 —CH₂CH₂OCH₂CH₂CH₃ 2 propoxyethyl 13 —Bn 2 benzyl 14

2 2-picolyl 15

2 2-thienylmethyl 16 —CH₂CH₂N(CH₂)₄ 2 2-(1-pyrrolidinyl)ethyl 17 —CH₂CH₂COOCH₂CH₃ 2 propoxylate ethyl ester 18 —Bn-4-Me 2 4-methylbenzyl 19

2 3-quinuclidinyl 20

2 2-(1-piperidino)-ethyl 21

2 2-(1-morpholino)-ethyl 22

2 1-indanyl 23 —Bn-3-OMe 2 3-methoxybenzyl 24 —Bn-3-Cl 2 3-chlorobenzyl 25

2 3-(1-morpholino)- propyl 26 —Bn-4-NMe₂ 2 4-(dimethylamino)-benzyl 27

2 piperonyl 28 —Bn-4-NO₂ 2 4-nitrobenzyl 29

2 3-(4-methyl-1- piperazinyl)-propyl 30 —Bn-3-CF₃ 2 3-trifluoromethyl- benzyl 31 —Bn-2,4-Cl 2 2,4-dichlorobenzyl 32 —Bn-4-SO₂Me 2 4-(methylsulfonyl)- benzyl 33 —Bn-3,4,5-OMe 2 3,4,5-trimethoxy- benzyl 1 —CH2OPh 1 phenoxymethyl 2 —CH2OCH(CH3)2 1 isopropoxymethyl 3 —CH2OPh-4-OMe 1 (4-methoxy)- phenoxymethyl 4 —CH2OPh-4-C(CH3)3 1 (4-t-butyl)- phenoxymethyl 5

1 2-furfuryloxymethyl 6 —CH2OPh-2-Me 1 2-methylphenoxy-methyl 7 —CH2OPh-4-Cl 1 4-chlorophenoxy-methyl 8 —Ph 1 phenyl 9

1 2-carbamyl-5-indolyl- oxymethyl 10 —CH2OPh-4-NO2 1 4-nitrophenoxymethyl

Example 3 Testing for In Vitro Activity

In vitro testing of the compounds of Table 1 was conducted as follows, using the assay protocol as described by Catterall, et al. (Catterall, W. A., et al., J Biol Chem, 254:11379-11387 (1979))

The following solutions were prepared:

1) Standard Binding Medium:

Component Amount (1 L preparation) albumin (BSA), 1 mg/mL 1000 mg. choline chloride, 130 mM 18.15 g. HEPES (N-2-hydroxyethyl-piperazine-N- 11.91 g. 2-ethanesulfonic acid), 50 mM glucose, 5.5 mM 990 mg. potassium chloride, 5.4 mM 400 mg. magnesium sulfate, 0.8 mM 96 mg.

The Standard Binding Medium was made in deionized water, adjusted to pH 7.4 with Tris base, and stored at 4° C. for up to 1 week.

2) Wash Buffer:

Component Amount (4 L prep.) choline chloride, 163 mM 79.659 g   HEPES, 5 mM 4.170 g  albumin (BSA), 1 mg/mL 3.500 g. calcium chloride, 1.8 mM 0.926 g. magnesium sulfate, 0.8 mM 0.337 g.

The Wash Buffer was made in deionized water, adjusted to pH 7.4 with Tris base, and stored at 4° C. for up to 1 week.

Membrane Preparation

The following solutions were prepared:

1) Membrane Solution A:

Component Amount (500 mL prep.) sucrose, 0.32M 54.77 g. sodium phosphate, monobasic, 5 mM 345 mg. p-toluencsulfonyl fluoride, 0.1 mM 9 mg.

The Membrane Solution A was made in deionized water, adjusted to pH 7.4 with sodium hydroxide, and stored at 4° C. for up to 2 months.

2) Membrane Solution B:

Component Amount (250 mL prep.) choline chloride, 260 mM 9.07 g. HEPES, 100 mM 5.96 g. glucose, 11 mM 495 mg. potassium chloride, 10.8 mM 202 mg. magnesium chloride, 1.6 mM 48 mg.

The Membrane Solution B was made in deionized water, adjusted to pH 7.4 with Tris base, and stored at 4° C. for up to 2 months.

Male Sprague-Dawley rat forebrain(s) were extracted, washed with Membrane Solution A, and homogenized in 9 mL/g of Membrane Solution A. The homogenate was centrifuged for 60 minutes at 17,000 g., and the supernatant liquid was removed. The membranes were resuspended in 3.3 mL/g of Membrane Solution A, then incubated at 4° C. for 30 minutes. 3.3 mL/g of Membrane Solution B was added, and the membranes were frozen in 1 mL aliquots at −80° C. for up to 4 days. The thus prepared Membrane Preparations were thawed on ice immediately before the Assay.

Assay

An assay was prepared in 96-well microtiter plates, having the following composition, and having 100 μL final volume:

-   60 μL Standard Binding Medium -   20 μL [³H]Saxitoxin: 10 nM (Amersham Pharmacia: TRK-877) -   10 μL of the test Compound: 100 μM (contains less than 2% DMSO) -   10 μL Membrane Preparation

The mixture was incubated for 25 minutes at room temperature (25° C.), then filtered over a Packard RG glass fiber filters, and washed 5× with 200 μL of Wash Buffer per well using a 96-well plate Cell Harvester (Packard). Immediately, the filter was dried and counted for 3 minutes. Non-specific binding is determined using 10 μL of 10 μM TTX (in place of the test Compound) and is 5-10% of the total binding.

Activity of the test compounds is expressed in terms of percent inhibition and, for some compounds, the concentration at which 50% inhibition is achieved (IC₅₀) (based on an 11-point dose-response curve. Results of this assay for the compounds in Table 1 are given in the following Table 3. A dash (-) indicates less than 10% inhibition was observed in this test.

TABLE 3 In vitro testing Compound no. % inhibition IC₅₀ (μM) 1 59 15 2 46 21 3 52 21 4 47 21 5 38 41 6 52 43 7 51 60 8 41 87 9 46 89 10 42 96 11 48 155 12 59 34 13 46 232 14 16 15 11 16 17 17 11 18 11 19 11 20 12 21 13 22 14 210 23 15 24 16 25 16 26 17 27 17 28 17 29 18 30 18 31 19 32 20 33 20 34 20 35 20 36 22 37 22 38 22 39 24 40 24 41 25 42 25 43 26 44 27 45 28 46 29 47 32 48 32 49 32 50 33 51 36 52 37 53 — 54 — 55 — 56 — 57 — 58 — 59 — 60 — 61 — 62 — 63 — 64 — 65 — 66 — 67 — 68 — 69 18 70 26 97 71 34 30 72 20 66 73 — 107 74 33 117 75 — 118 76 — 100 77 27 81 78 17 67

Example 5 Testing for in vivo Activity

Compounds of Table 1 were tested for activity in vivo by the following method, using modifications of the assay protocols described by Drasner et al. (Drasner, K., et al., Anesthesiology, 80:847-852 (1994); Sakura, S., et al., Anesthesiology, 85:1184-1189 (1996))

Male Sprague-Dawley rats (200-300 g) were implanted with intrathecal catheters according to the procedure described by Drasner et al. Rats were placed in a horizontal restraint-and-sensory-function was assessed using the-tail-flick test. The tail was placed over a slit through which a beam of light was projected with latency to movement as the measured end-point. The heat was shut off if there was no response by 8 seconds (cut-off).

Test compounds were dissolved at the desired concentration in aqueous 2.5% glucose solution (“Glu”) (or aqueous 10% polyethylene glycol (“PEG”) (average MW=1000) solution in cases of low solubility). Rats were given an intrathecal injection of the test compound of 60 μL at a rate of approximately 1 μL/sec. Tail sensory function was assessed 5 minutes, 1 hour, 1 day, and 4 days post-injection.

The results of this assay arc shown in the following Table 4. Tail sensory function is expressed in terms of % Maximal Possible Effect (MPE), which is defined as calculated as {(tail-flick latency−baseline)/(cut-off−baseline)}×100. Thus, a compound producing complete anesthesia or unresponsiveness to the heat stimulus would receive a score of 100.

TABLE 4 In vivo testing Animals Average Average Tested % MPE % MPE Compound Conc. (M) Formulation (N) 5 minutes Day 4 1 3.30  10% PEG 2 100 3 2 4.53  10% PEG 2 100 1 3 4.00  10% PEG 3 100 −2 3 4.23 2.5% Glu 3 76 6 4 4.30  10% PEG 2 100 −2 5 7.95  10% PEG 2 100 7 6 4.65 saline 2 93 −5 6 4.65  10% PEG 2 80 −6 6 11.62  10% PEG 2 100 1 6 11.62 2.5% Glu 4 100 21 7 8.00  10% PEG 2 100 32 8 7.00  10% PEG 2 100 1 8 14.40  10% PEG 2 100 18 8 14.40 2.5% Glu 3 100 47 9 4.05  10% PEG 2 100 34 10 4.00 2.5% Glu 3 26 19 11 3.51  10% PEG 2 34 18 22 12.00  10% PEG 2 100 11 22 12.00 2.5% Glu 2 100 8 22 24.20 2.5% Glu 2 100 −2 70 4.83  10% PEG 3 83 4 71 5.90  10% PEG 2 100 2 78 2.93 2.5% Glu 2 11 −4 — —  10% PEG 2 5 −3 — — 2.5% Glu 2 2 1

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. 

1. A method for producing anesthesia or analgesia in a subject comprising administering to said subject an anesthetically or analgesically effective amount of a compound having the formula

in which: R₁ is (a) substituted or unsubstituted alkyl; (b) substituted or unsubstituted cycloalkyl; (c) substituted or unsubstituted alkenyl; (d) adamantyl; (e) substituted or unsubstituted phenyl; a 5- or 6-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; (g) substituted or unsubstituted benzyl; (h) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; or (i) CH₂XR₅, where X is oxygen, sulfur, —NH— or —CH₂— and R₅ is substituted or unsubstituted alkyl; substituted or unsubstituted cycloalkyl; substituted or unsubstituted phenyl; substituted or unsubstituted benzyl; 2-carbsunide-indolyl; or a 5-to 9-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; R₂ is (a) substituted or unsubstituted alkyl; (b) substituted or unsubstituted cycloalkyl; (c) substituted or unsubstituted alkenyl; (d) substituted or unsubstituted alkoxyalkyl (e) a 5- or 6-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, (f) —(CH₂)_(n)R₃, where R₃ is (i) a 5- to 9-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; (ii) —NR₆R₇ where R₆ and R₇ are independently selected from hydrogen, methyl, ethyl and benzyl; or (iii) COOR₈ where R₈ is alkyl; and n is 2 or 3; (h) substituted or unsubstituted phenyl; (i) substituted or unsubstituted benzyl; (f) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; or (k) methylene-1-naphthyl; and R₄ is a) hydrogen; b) (CH₂)_(m)COOR₁₅ where R₁₅ is alkyl or substituted alkyl; and m is 0, 1 or 2; c) CONR₁₆R₁₇ where R₁₆ and R₁₇ are independently (i) hydrogen; (ii) alkyl or substituted alkyl; (iii) cycloalkyl; (iv) alkoxyalkyl; (v) a 5- to 10-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; (vi) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; (vii) substituted or unsubstituted phenyl; (viii) (CH₂)_(p)R₁₈ where R₁₈ is a 5-or 6-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, and p is 1, 2 or 3; (ix) optionally substituted benzyl; or (x) an aralkyl group comprising a chain of from 1 to 4 methylene groups substituted by one or two phenyl groups; d) C₁—C₄ alkoxy; e) optionally substituted phenoxy; f) SO2NR19R₂₀ where R₁₉ and R₂₀ are independently hydrogen, optionally substituted alkyl or phenyl; g) NR₂₁R₂₂; h) COR₂₃ where R₂₃ is alkyl or is NR₂₁R₂₂; i) COOR₂₃ where R₂₃ is hydrogen, alkyl, or benzyl; j) SO2R₂₅ where R₂₅ is alkyl or NR₂₁R₂₂; wherein R₂₁ and R₂₂ are independently hydrogen, alkyl, optionally substituted phenyl or optionally substituted benzyl; or a pharmaceutically acceptable salt thereof; or a composition containing an anesthetically or analgesically effective amount of said compound or salt.
 2. A method according to claim 1 in which R₁ is (a) C₁—C₆ alkyl, optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COOH and COOCH₃; (b) C₂—C₆ alkenyl optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COON and COOCH₃; (c) C₃—C₆ cycloalkyl optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COOH and COOCH₃; (d) adamantyl; (e) optionally substituted phenyl in which the substituents are selected from mono-and dihalo, mono- and di-(C₁—C₄ alkoxy), mono- and di-(C1-C2 alkylthio), C₁—C₂ alkyleneoxy; C₁—C₂ alkylenedioxy, mono-and di-(C₁—C₄ alkyl), mono- and di-(trifluoromethyl), mono- and di-(C₁—C₄ hydroxyalkyl), mono-and di-(C₁—C₄ alkoxyalkyl), mono- and di-hydroxy, mono- and di-cyano, mono- and di-(COCH₃), and mono- and di-NHR₂₆; (f) a 5- or 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, C₁—C₄ alkyl, C₁—C₄ alkoxy, oxo and hydroxy; (g) optionally substituted benzyl in which the substituents are selected from mono-and dihalo, mono- and di-(C₁—C₄ alkoxy), mono- and di-(C₁—C₄ alkylthio), C₁—C₂ alkyleneoxy; C₁—C₂ alkylenedioxy, mono-and di-(C₁—C₄ alkyl), mono- and di-(trifluoromethyl), mono- and di-(C₁—C₄ hydroxyallcyl), mono-and di-(C₁—C₄ alkoxyalkyl), mono- and di-hydroxy, mono- and di-cyano, mono- and di-(COCH₃), and mono- and di-NHR₂₆; (g) naphthyl; or (h) CH₂XR₅, where X is oxygen, sulfur, —NH— or —CH₂— and R₅ is selected from (i) C₁—C₆ alkyl; (ii) C₃—C₆ cycloalkyl; (iii) optionally substituted phenyl in which the substituents are selected from mono- and di-(C₁—C₄ alkyl), mono- and dihalo, mono- and di-(C₁—C₄ alkoxy), C₁—C₂ alkyleneoxy, C₁—C₂ alkylenedioxy, mono- and di-(trifluoromethyl), nitro, hydroxy, mono- and di-(C₁—C₄ hydroxyalkyl), mono- and di-(C₁—C₄ alkoxyalkyl), mono- and di-hydroxy, mono- and dicyano, mono- and di-(COCH₃), and mono- and di-NHR₂₆; (iv) benzyl; (v) 2-carbamide-indolyl; or (vi) a 5- to 9-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur optionally substituted by from 1 to 3 groups independently selected from halo, C₁—C₄ alkyl, C₁—C₄ alkoxy, oxo and hydroxy; R₂ is (a) C₁—C₁₂ alkyl optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COOH and COOCH₃; (b) C₂—C₈ cycloalkyl optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COOH and COOCH₃; (c) C₂—C₁₂ alkenyl optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COOH and COOCH₃; (d) C₂—C₁₂ alkoxyalkyl; (e) a 5- or 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, C₁—C₄ alkyl, C₁—C₄ alkoxy, oxo, and hydroxy; (f) —(CH₂)_(n)R₃, where R3 is (i) a 5- to 9-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, C₁—C₄ alkyl, C₁—C₄ alkoxy, oxo, and hydroxy; (ii) —NR₆R₇ where R₆ and R₇ are independently selected from hydrogen, methyl, ethyl and benzyl; or (iii) COORS where R₈ is C₁—C₄ alkyl; and n is 2 or 3; (g) optionally substituted phenyl, where the substituents are independently selected from mono- and di-(C₁—C₄ alkyl); mono- and dihalo; mono-, di-, and tri-C₁—C₄ alkoxy); mono- and dicyano; nitro; methylsulfonyl; mono-, di-, and tri-(trifluoromethyl); C₁—C₂ alkyleneoxy; C₁—C₂ alkylenedioxy; —(CH₂)_(q)COOR₉ where R₉ is C₁—C₄ alkyl; or —(CH₂)_(q)NR₁₀R₁₁ where R₁₀ and R₁₁ are independently hydrogen, (C₁—C₄) alkyl, COR₁₂ where R₁₂ is C₁—C₄ alkyl, SO₂R₁₃ where R₁₃ is C₁—C₄ alkyl, or COOR₁₄ where R₁₄ is C₁—C₄ alkyl and CONR′R″; and q is an integer from 1 to 4; (h) optionally substituted benzyl, where the substituents are selected from mono-, di-, and tri-(C₁—C₄) alkyl; mono-, di-, and tri-halo; mono, di-, and tri-(C₁—C₄ alkoxy); mono-, di-, and tri-(C₁—C₄ alkylthio); mono- and di-cyano; nitro; methylsulfonyl; mono-, di-, and tri-(trifluoromethyl); mono-, di-, and tri-COOR′; mono-, di-, and tri-CONR′R″; mono-, di-, and tri-NR₂₇R₂₈ where R₂₇ and R₂₈ are independently selected from hydrogen, C₁—C₄ alkyl, acetyl, and methylsulfonyl; C₁—C₂ alkyleneoxy; C₁—C₂ alkylenedioxy; and mono-, di-, and tri-(C₁—C₆ alkoxyalkyl); (j) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; or (k) methylene-1- or 2-naphthyl; and R₄ is (a) hydrogen; (h) (CH₂)_(m)COOR′ where m is 0, 1 or 2; (c) CONR₁₆R₁₇ where R₁₆ and R₁₇ are independently (i) hydrogen; (ii) C₁—C₅ alkyl optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COOH and COOCH₃; (iii) C₃—C₆ cycloalkyl; (iv) C₂—C₈ alkoxyalkyl; (v) a 5- to 10-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur optionally substituted by from 1 to 3 groups independently selected from halo, hydroxy, oxo, C₁—C₄ alkyl, C₁—C₄ alkoxy, COCH₃, COOR′, and NR₂₉R₃₀ where R₂₉ and R₃₀ are independently selected from hydrogen, C₁—C₄ alkyl, acetyl, or methylsulfonyl; (vi) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; (vii) (CH₂)_(p)R₁₈ where R₁₈ is a 5- or 6- membered saturated or unsaturated heterocyclic group having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, hydroxy, C₁—C₄ alkyl, C₁—C₄ alkoxy and oxo, and p is 1, 2 or 3; (viii) phenyl optionally substituted by one or more groups independently selected from mono-, di-, and tri- halo, mono-, di-, and tri-hydroxy, mono-, di-, and tri-(C₁—C₄ alkyl), C₁—C₂ alkyleneoxy, C₁—C₂ alkylenedioxy, COOR′, and NR₂₉R₃₀ where R₂₉ and R₃₀ are independently selected from hydrogen, C₁—C₄ alkyl, acetyl, and methylsulfonyl; (ix) optionally substituted benzyl where the substituents are selected from mono-, di-, and tri-(C₁—C₄ alkyl); mono-, di-, and tri- halo; mono-, di-, and tri-(C₁—C₄ alkoxy); nitro; methylsulfonyl; mono-, di-, and tri-(trifluoromethyl); NR′R″; C₁—C₂ alkyleneoxy; C₁—C₂ alkylenedioxy; or (x) an aralkyl group comprising a chain of from 1 to 4 methylene groups substituted by one or two phenyl groups; (d) C₁—C₄ alkoxy; (e) optionally substituted phenoxy, where the substituents are independently selected from mono- and di-(C₁—C₄) alkyl; mono- and dihalo; mono-, di-, and tri-(C₁—C₄ alkoxy); cyano; nitro; methylsulfonyl; mono-, di-, and tri- trifluoromethyl; C₁—C₂ alkyleneoxy; C₁—C₂ alkylenedioxy; —(CH₂),COOR₉ where R₉ is C₁—C₄ alkyl; or —(CH₂)_(r)NR₃₀R₃₁ where R₃₀ and R₃₁ are independently hydrogen, (C₁—C₄)alkyl, COR₃₂ where R₃₂ is C₁—C₄ alkyl, SO₂R₃₃ where R₃₃ is C₁—C₄ alkyl, or COOR₃₄ where R₃₄ is C₁—C₄ alkyl; (i) SO₂NR₃₅R₃₆ where R₃₅ and R₃₆ are independently hydrogen, C₁—C₄ alkyl or phenyl; or (g) NR₃₇R₃₈ where R₃₇ and R₃₈ are independently hydrogen; C₁—C₄ alkyl; phenyl; COR₃₉ where R₃₉ is C₁—C₄₇ alkyl; or SO₂R₄₀ where R₄₀ is hydrogen or C₁—C₄ alkyl; wherein R₂₆ is COCH₃, SO₂CH₃, SO₂C₆H₃, COOR' or CONR′R″; and wherein R′ and R″ are independently hydrogen or C₁—C₄ alkyl; and pharmaceutically acceptable salts thereof.
 3. A method according to claim 1 in which R₁ is phenyl, substituted phenyl, a 5- or 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur optionally substituted by from 1 to 3 groups independently selected from halo, alkyl, alkoxy, oxo or hydroxy, or CH₂XR₅; R₂ is benzyl, substituted benzyl, C₂—C₄ alkyl, or —(CH₂)₂R₃, where R₃ is a 5- to 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; and R₄ is hydrogen.
 4. A method according to claim 1 in which R₁ is phenyl.
 5. A method according to claim 1 in which R₁ is substituted phenyl.
 6. A method according to claim 1 in which R₁ is mono- or dihalophenyl.
 7. A method according to claim 6 in which R₁ is 3,4-dichlorophenyl.
 8. A method according to claim 1 in which R₁ is a 5- or 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, C₁—C₄ alkyl, C₁—C₄ alkoxy, oxo or hydroxy.
 9. A method according to claim 1 in which R₁ is thienyl.
 10. A method according to claim 1 in which R₁ is CH₂XR₅, where X is oxygen, sulfur, —NH— or —CH₂— and R₅ is selected from (i) C₁—C₆ alkyl; (ii) C₃—C₆ cycloalkyl; (iii) optionally substituted phenyl in which the substituents are selected from mono- and di-(C₁—C₄ alkyl), mono- and dihalo, mono- and di-(C₁—C₄ alkoxy), C₁—C₂ alkyleneoxy, C₁—C₂ alkylenedioxy, mono- and di-(trifluoromethyl), nitro, hydroxy, mono- and di-(C₁—C₄ hydroxyalkyl), mono- and di-(C₁—C₄ alkoxyalkyl), mono- and di-hydroxy, mono- and dicyano, mono- and di-(COCH₃), and mono- and di-NHR₂₆; (iv) benzyl; (v), 2-carbamide-indolyl; or (vi) a 5- to 9-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, C₁—C₄ alkyl, C₁—C₄ alkoxy, oxo and hydroxy.
 11. A method according to claim 10 in which R₁ is CH₂XR₅ and R₅ is phenyl, substituted phenyl, or benzyl.
 12. A method according to claim 10 in which X is oxygen.
 13. A method according to claim 12 in which R₅ is benzyl, phenyl, or substituted phenyl.
 14. A method according to claim 13 in which R₅ is phenyl.
 15. A method according to claim 13 in which R₅ is 4-chlorophenyl.
 16. A method according to claim 13 in which R₃ is benzyl.
 17. A method according to claim 1 in which R₂ is benzyl.
 18. A method according to claim 1 in which R₂ is substituted benzyl.
 19. A method according to claim 2 in which R₂ is benzyl or substituted benzyl
 20. A method according to claim 19 in which R₂ is benzyl substituted by a C₁—C₄ alkyl group, a C₁—C₄ alkoxy group, or a halogen.
 21. A method according to claim 19 in which R₂ is 4-methylbenzyl.
 22. A method according to claim 19 in which R₂ is 4-methoxybenzyl.
 23. A method according to claim 19 in which R₂ is 4-fluorobenzyl.
 24. A method according to claim 1 in which R₂ is a C₂—C₄ alkyl group.
 25. A method according to claim 24 in which R₂ is ethyl.
 26. A method according to claim 24 in which R₂ is n-butyl.
 27. A method according to claim 1 in which R₂ is —(CH₂)₂R₃, where R₃ is a 5- to 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur.
 28. A method according to claim 27 in which R₃ is -piperidino.
 29. A method according to claim 1 in which R₄ is hydrogen.
 30. A method according to claim 1, further providing that: if R₁ is 4-chlorophenoxymcthyl and R₄ is hydrogen, then R₂ is not methyl or 2-(N,N,-diethylamino)ethyl; if R₁ is phenoxymethyl and R₄ is hydrogen, then R₂ is not 2-(N,N,-dicthylamino)ethyl; if R₁ is phenyl and R₄ is hydrogen, then R₂ is not methyl; if R₁ is 4-chlorophenyl and R₄ is hydrogen then R₂ is not methyl, n-butyl or allyl; if is 4-bromophenyl and R₄ is hydrogen, then R₂ is not n-butyl or benzyl; if R₁ is 4-methylphenyl and R₄ is hydrogen, then R₂ is not n-propyl; if R₁ is 2-furyl and R₄ is hydrogen, then R₂ is not benzyl or (4-chlorobenzyl); if R₁ is methyl and R₄ is hydrogen, then R₂ is not methyl or ethyl; if R₁ is t-butyl and R₄ is hydrogen, then R₂ is not 4-chlorobenzyl; and if R₁ is 1-naphthyl and R₄ is hydrogen, then R₂ is not methyl.
 31. A method according to claim 1, further providing that: if R₁ is 4-chlorophenoxymethyl, then R₂ is not methyl or 2-(N,N,-diethylamino)ethyl; if R₁ is phenoxymethyl, then R₂ is not 2-(N,N,-diethylamino)ethyl; if R₁ is phenyl, then R₂ is not methyl; if R₁ is 4-chlorophenyl, then R₂ is not methyl, n-butyl or allyl; if R₁ is 4-bromophenyl, then R₂ is not n-butyl or benzyl; if R₁ is 4-methyiphenyl, then R₂ is not n-propyl; if R₁ is 2-furyl, then R₂ is not benzyl or (4-chlorobenzyl); if R₁ is methyl, then R₂ is not methyl or ethyl; if R₁ is t-butyl, then R₂ is not 4-chlorobenzyl; and if R₁ is 1-naphthyl, then R₂ is not methyl.
 32. A method according to claim 1 for producing local or regional anesthesia. 